title: 2-Aminobenzimidazoles as potent ITK antagonists: trans-stilbene-like moieties targeting the kinase specificity pocket.
abstract: Based on the information from molecular modeling and X-ray crystal structures, the kinase specificity pocket of ITK could be occupied upon extension of the right-hand-side of the 2-benzimidazole core of the inhibitors. 2-Aminobenzimidazoles with a trans-stilbene-like extension were designed and synthesized as novel ITK antagonists. Significant improvement on binding affinity and cellular activity were obtained through the trans-stilbene-like antagonists. Several compounds showed inhibitory activity in an IL-2 functional assay.
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877, USA. ho-yin.lo@boehringer-ingelheim.com
authors.forename: Ho Yin
authors.initials: HY
authors.lastname: Lo
authors.forename: Jörg
authors.initials: J
authors.lastname: Bentzien
authors.forename: Roman W
authors.initials: RW
authors.lastname: Fleck
authors.forename: Steven S
authors.initials: SS
authors.lastname: Pullen
authors.forename: Hnin Hnin
authors.initials: HH
authors.lastname: Khine
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Woska
authors.forename: Stanley Z
authors.initials: SZ
authors.lastname: Kugler
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Kashem
authors.forename: Hidenori
authors.initials: H
authors.lastname: Takahashi
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015195:Drug Design; D015394:Molecular Structure; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013267:Stilbenes / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D013267:Stilbenes; C027391:2-aminobenzimidazole; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases